Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:16])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].C(O)CO.[F-:21].[K+]>CCOCC>[F:21][CH2:2][CH:3]=[C:4]([CH3:16])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CCCC(C)CC=CC(C)=CCBr
Reactant: [F-]
Agent: [K+]
Solvent: OCCO
Solvent: CCOCC
Product: CC(C)=CCCC(C)CC=CC(C)=CCF

Procedure:
A mixture of 33 g. of 1-bromo-3,7,11-trimethyldodeca-2,4,10-triene and 100 ml. of dry ethylene glycol is slowly added with stirring, to a suspension of 11.5 g. of potassium fluoride in 30 ml. of dry ethylene glycol and heated to about 120°, under an inert atmosphere. When addition is completed, the reaction mixture is stirred for about an additional 16 hours while maintaining the temperature at 120°. Then the mixture is cooled and 200 ml. of ether added. The mixture is washed thoroughly with water and the ether phase dried over sodium sulfate and solvent evaporated under reduced pressure to yield 1-fluoro-3,7,11-trimethyldodeca-2,4,10-triene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[NH2:42][C:43]1[S:44][CH:45]=[C:46]([CH3:48])[N:47]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:42][C:43]2[S:44][CH:45]=[C:46]([CH3:48])[N:47]=2)=[O:40])=[CH:18][CH:17]=1
Reactant: Cc1csc(N)n1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4nc(C)cs4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (40 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (20 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 2-amino-4-methylthiazole (17 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated, and the residue was then purified by chromatography (chloroform:acetone=2:1) to give the title compound (11.8 mg, yield 20.0%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22](OC)=[O:23])[CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CCOCC.O>[CH2:7]([O:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[CH2:22][OH:23])[CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC/C=C\CCCOc1cccc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCCC/C=C\CCCOc1cccc(CO)c1
Yield: 99.9 %

Procedure:
35 mg of lithium aluminum hydride (922 μmol) are added, at 0° C., to 140 mg of 15 (460 μmol) in ether (3 mL). After reaction for 1 hour 30 minutes, the reaction medium is diluted with ether and hydrolyzed with two drops of water. After filtering through Celite, drying over Na2SO4 and concentrating, 127 mg of a colorless oil are isolated, i.e. a yield of 99%.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[Br:12][C:13]1[CH:14]=[C:15]([C:19]2([F:32])[C:24]([CH3:26])([CH3:25])[O:23][C:22](OCC)=[N:21][S:20]2(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C:19]2([F:32])[C:24]([CH3:25])([CH3:26])[O:23][C:22]([NH:1][C@H:2]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:3][CH2:4][OH:5])=[N:21][S:20]2(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](CCO)c1ccccc1
Reactant: CCOC1=NS(=O)(=O)C(F)(c2cccc(Br)c2)C(C)(C)O1
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
In a round-bottom flask, 42 mg of 5-(3-bromophenyl)-2-ethoxy-5-fluoro-6,6-dimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide was dissolved under inert gas in 0.2 ml of dichloromethane and admixed with 20 mg of (S)-3-amino-3-phenylpropan-1-ol. After stirring at room temperature for 18 hours, the conversion was checked by LCMS. Since only traces of the product had formed, the reaction mixture was stirred at 100° C. for a further 4.5 hours. After the removal of the solvent under reduced pressure, the crude product was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (13.1 mg) with a molecular weight of 485.4 g/mol (C20H22BrFN2O4S); MS (ESI): m/e=485 (M+H+).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[CH2:39][CH2:40][NH2:41]>>[Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:41][CH2:40][CH2:39][C:38]1[CH:42]=[CH:43][CH:44]=[C:36]([O:35][CH3:34])[CH:37]=1)=[O:19])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: COc1cccc(CCN)c1
Product: COc1cccc(CCNC(=O)c2cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)c2)c1
Yield: 98 %

Procedure:
The title compound was prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) and 3-methoxyphenethylamine, using a similar method to that of preparation 158, in 98% yield.
Reaction SMILES: [CH3:1]C(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.[Cl:36][C:37]1[C:60]([Cl:61])=[CH:59][CH:58]=[CH:57][C:38]=1[CH2:39][C:40]1[C:41]([OH:56])=[N:42][NH:43][C:44]=1[N:45]1[C:53](=[O:54])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]1=[O:55]>C1COCC1.C(Cl)Cl>[Cl:36][C:37]1[C:60]([Cl:61])=[CH:59][CH:58]=[CH:57][C:38]=1[CH2:39][C:40]1[C:41]([O:56][CH3:1])=[N:42][NH:43][C:44]=1[N:45]1[C:46](=[O:55])[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:53]1=[O:54]
Reactant: O=C1c2ccccc2C(=O)N1c1[nH]nc(O)c1Cc1cccc(Cl)c1Cl
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1n[nH]c(N2C(=O)c3ccccc3C2=O)c1Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A mixture of DIAD (1.14 g, 5.67 mmol), PPh3 (1.49 g, 5.67 mmol) and methanol (0.18 g, 5.67 mmol) in THF (30 mL) was stirred at 0° C. for 1 h. Then, the mixture was added dropwise to a solution of 2-(4-(2,3-dichlorobenzyl)-3-hydroxy-1H-pyrazol-5-yl)isoindoline-1,3-dione (2 g, 5.15 mmol) in THF (500 mL) and DCM (500 mL), and the mixture was stirred at room temperature for 2 h. It was quenched with water (50 mL), and the solvent was evaporated in vacuo to dryness. The residue was purified by silica gel chromatography eluted with EA:PE=1:1 to give the titled compound (620 mg, 30%) as a white solid. LC/MS: MS (ES+) m/e 402 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.74 (s, 2H), 3.84 (s, 3H), 7.08 (d, J=4.8 Hz, 2H), 7.27-7.31 (m, 1H), 7.94 (s, 5H), 12.27 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In analogy to the procedure described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-(2-benzyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate; MS: 568 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N+:7]=1[O-:21]
Reactant: COC(=O)Cc1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To methyl 2-(6-chloropyridin-3-yl)acetate (2.5 g) in DCM (100 mL) was added mCPBA (4.6 g). The resulting reaction mixture was stirred at room temperature for 4 hr. The organic phase was washed with sat. NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by flash chromatography to afford the title product (2.5 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[Cl:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[CH:24]=[C:23]([CH2:25]Cl)[CH:22]=[CH:21][N:20]=2)=[CH:13][C:12]=1[O:27][CH3:28]>>[Cl:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[CH:24]=[C:23]([CH2:25][N:1]3[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]3)[CH:22]=[CH:21][N:20]=2)=[CH:13][C:12]=1[O:27][CH3:28]
Reactant: NC(=O)C1CCNCC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1Cl
Product: COc1cc(-c2cc(CN3CCC(C(N)=O)CC3)ccn2)cc(OC)c1Cl

Procedure:
Piperidine-4-carboxamide (301 mg) and 2-(4-chloro-3,5-dimethoxyphenyl)-4-chloromethylpyridine (600 mg) were coupled in the same manner as described in Example 2 to give the title compound.
Reaction SMILES: [N:1]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:6]=[CH:5][N:4]([C:7]([O:9][CH2:10][CH:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[CH2:3][CH2:2]1.[CH2:31]([Zn]CC)C.ICI>CCOCC>[CH:6]12[CH2:31][CH:5]1[N:4]([C:7]([O:9][CH2:10][CH:11]1[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]3[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:8])[CH2:3][CH2:2][N:1]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)N1C=CN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C2CC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a pre-dried round bottom flask, tert-butyl 9H-fluoren-9-ylmethyl 2,3-dihydropyrazine-1,4-dicarboxylate (1.5 g, 3.69 mmol) was dissolved in anhydrous ether (80 ml) under N2. Diethylzinc (27.4 ml, 27.4 mmol) in ether (1M) was added in via syringe. Diiodomethane (1.904 ml, 23.60 mmol) was added. Let reaction stir at room temperature overnight. On next day, reaction was quenched by adding 5 mL of saturated aqueous NH4Cl. Reaction mixture was filtered over a pad of Celite® and filtering cake was washed with ether (25 mL×2). Then layers were separated and aqueous portion was extracted with ether (50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4. Concentration at reduced pressure afforded crude product that was purified by silica gel column chromatography (40 gram silica gel column, eluted with 0-100% EtOAc/Hexane gradient). Removing solvent gave the title compound. 1H NMR (ppm) (500 MHz, CDCl3): δ 7.76 (2H, d, J=7.59 Hz), 7.66-7.53 (2H, m), 7.40 (2H, t, J=7.50 Hz), 7.31 (2H, t, J=7.45 Hz), 4.52-4.44 (2H, m), 4.26 (1H, t, J=7.13 Hz), 3.62-2.90 (6H, m), 1.50 (9H, s), 1.25-0.89 (1H, m). 0.55-0.39 (1H, m); LC/MS (M+23)+=443.13;
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[O:3])[CH3:2].O.[CH:9](=[C:11]([C:17](=O)[CH2:18]Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][CH:10]=[C:9](/[C:11](=[CH:17]/[CH3:18])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(N)=S
Reactant: CC=C(C(=O)CCl)C(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C(\C(=O)OCC)c1csc(NC(C)=O)n1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
14.6 parts by weight of acetylthiourea, 30 parts by volume of water and 50 parts by volume of N,N-dimethylformamide are heated up to 85° C. under nitrogen. 22.9 parts by weight of ethyl 2-ethylidene-4-chloro-3-oxobutyrate are then added at this temperature in the course of 40 minutes. The mixture is stirred at 80° to 85° C. for 1 hour and then cooled to 15° C., and, after 10 minutes, the precipitate which has separated out is filtered off with suction. The precipitate is suspended once in 34.5 parts by volume of water, filtered off with suction again and washed twice more with water. The crude product is dried and then extracted by stirring once in a mixture of 13.8 parts by volume of water and 41.8 parts by volume of ethanol for 10 minutes, filtered off with suction and rinsed with ethanol/water (3/1). After drying, 8.8 parts by weight of a pure product are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][N:11]([CH3:15])[C:10](=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O>[Cl:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][N:11]([CH3:15])[C:10](=[O:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Cc1nn(C)c(=O)cc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(C)c(=O)cc1-c1ccc(OCCCCl)cc1
Yield: 98 %

Procedure:
A solution of the product from step 2 (710 mg, 3.29 mmol), K2CO3 (1.36 g, 3.0 eq.) and 3-bromo-1-chloropropane (0.39 mL, 1.2 eq.) in CH3COCH3 (30 mL) was heated to 80° C. overnight. The mixture was then filtered, washed with acetone and concentrated to dryness to afford the product of step 3 (950 mg, 98%): MS m/z 293 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].[Na].C[O:6][C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:26])[NH:15][C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(O)(=O)C>CO.O.C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1>[OH:3][NH:2][C:7](=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:15][C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:26]
Reactant: COC(=O)CCCCCCC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: NO
Agent: Cl
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(CCCCCCC(=O)NC12CC3CC(CC(C3)C1)C2)NO
Reaction time: 24 h
Yield: 68 %

Procedure:
To a first solution of hydroxylamine hydrochloride (66 mg, 0.950 mmol) and phenolphthalein (0.5 mg) in methanol (3 mL), was added dropwise a second solution of sodium metal (33 mg, 1.435 mmol) in methanol (3 mL) via additional funnel until a pink endpoint was reached and precipitate appeared. To the reaction mixture was added a solution of 7-(adamantan-1-yl-carbamoyl)-heptanoic acid methyl ester (152 mg, 0.474 mmol) in methanol (4 mL) was added, followed by the remainder of the second solution of sodium metal in methanol. The resulting reaction was allowed to stir for 24 hours, then the reaction mixture was diluted with water (15 mL), followed by glacial acetic acid (0.2 mL) with stirring. The resulting precipitate was suction filtered and rinsed using water, then dried at room temperature under vacuum to provide a crude residue which was purified by recrystallization from dichloromethane/hexane to provide Compound 17 (104 mg, 68% yield). 1H NMR (300 MHz, CD3OD) δ 7.31 (br s, 1H), 2.09 (t, J=7.5 Hz, 2H), 2.08-1.98 (m, 11H), 1.71 (m, 6H), 1.59 (m, 4H), 1.33 (m, 4H). 13C NMR (75 MHz, CD3OD) δ 175.7, 173.1, 52.8, 42.5, 38.0, 37.7, 33.9, 31.1, 30.00, 29.96, 27.2, 26.8.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:44]=[N+:45]=[N-:46])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[N:44]([CH2:28][C:26]1[N:27]=[C:23]([N:21]2[CH2:22][CH:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:20]2)[S:24][CH:25]=1)=[N+:45]=[N-:46]
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (1.02 g, 2.39 mmol) (obtained as described in Reference Example 2(2)) in tetrahydrofuran (50 ml) were added diphenylphosphoryl azide (0.8 ml, 3.71 mmol), triphenylphosphine (950 mg, 3.62 mmol) and 40% diethylazodicarboxylate in toluene solution (1.32 g, 3.59 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred in an ice bath for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (8:1) as the eluant to afford 1-(4-azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (1.06 g, yield 99%) as colorless syrup.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.C(O[CH:9]([O:17]CC)[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15]C)C.[C:20](=O)([O-])[O-].[K+].[K+]>ClC(Cl)C>[CH3:20][CH:12]([O:11][C:10](=[CH:3][N:2]([CH3:5])[CH3:1])[CH:9]=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: CN(C)C=O
Reactant: CCCCCOCC(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: CCCC(C)OC(C=O)=CN(C)C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution prepared by adding 30 g of dried N,N-dimethylformamide to dried dichloroethane was cooled to 5° C. or lower, After a solution containing 63 g of phosphorus oxychlorate dissolved in dichloroethane was added to the cooled solution dropwise, the mixture was stirred for 30 minutes at 5° C. or lower. Subsequently, to the reaction solution was added a dichloroethane solution of the compound (54), and the resulting mixture was stirred for 30 minutes at room temperature and then for one hour at 70° C. After the reaction solution was cooled to room temperature, the reaction solution was poured into ice water and was then made basic by addition of potassium carbonate. The reaction solution was then concentrated under reduced pressure. The concentrate was warmed and stirred, and was then extracted with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent used was distilled out. The residue was distilled under reduced pressure to obtain 2-(1-methylbutyloxy)-3-dimethylaminoacrolein (55) (boiling point: 150° to 155° C./5 mmHg).
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:50]([O:57][C:58](=[O:72])[C:59](Br)([CH3:70])[CH2:60][CH2:61][O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CC#N>[CH2:50]([O:57][C:58](=[O:72])[C:59]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)([CH3:70])[CH2:60][CH2:61][O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(Br)(CCOCc1ccccc1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CCOCc4ccccc4)C(=O)OCc4ccccc4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (100 mg, 0.307 mmol) and Cs2CO3 (200 mg, 0.615 mmol) in CH3CN (1 mL) was added a solution of 4-benzyloxy-2-bromo-2-methylbutyric acid benzyl ester (0.345 mmol) in CH3CN (7 mL) and stirring at reflux temperature was continued for 3 h. After cooling to RT, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM) affording 4-Benzyloxy-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylbutyric acid benzyl ester as a pale orange gum (36 mg, 19%). LCMS: RT 4.28 min [M+H]+ 622.3
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[OH:36])=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:38].[Na]>ClCCl.CO>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[OH:36])=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O-:8])=[O:7])[CH2:2][CH2:3][CH3:4].[Na+:38]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3O)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3O)cc2)cc1)C(=O)[O-]

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(2′-hydroxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (345 mg), which is the product of Example 44, was reacted with aqueous sodium hydroxide solution (1N, 2.82 ml) and the reaction mixture was treated to afford the crude free acid which was subjected to chromatography on a silica gel thin layer plate using dichloromethane/methanol=10/1 as the eluant. The product was converted to the sodium salt to give the title compound (200 mg) as colorless crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>>[N:20]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]4[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]4)=[CH:7][CH:8]=3)=[CH:13][CH:14]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCCC1
Product: O=C(c1ccc(-c2ccc(OCCCN3CC[C@@H](O)C3)cc2)cc1)N1CCCC1

Procedure:
1-{[4′-(3-Chloropropoxy)[1,1′-biphenyl]-4-yl]carbonyl}pyrrolidine and (3R)-3-pyrrolidinol were processed as described in Example 159 to provide the title compound.